Summary: We have investigated the regulation of host cell genes by HIV infection of primary human macrophages. Using commercial gene grids we have screened in parallel primary human macrophages either infectred with HIV or uninfected. From these we have identified hundreds of genes which appear to be regulated by HIV infection. We are now confirming these by "TAQ-Man" PCR analysis, focusing first on genes which are involved in apoptosis. Currently we are doing similar studies on macrophages treated with HIV tat protein. We have recently published interesting findings concerning genes involved in protecting macrophages from HIV-induced cell death and concerning upregulation by HIV og macrophage genes responsible for killing neighboring, uninfected cells during HIV infection. Further genes involved in programmed cel death are being studied with respect to HIV infection. In other studies, we are investigating the role of numerous HIV genes using a technique of hyper-fine linker insertion mutagenesis. Using this technique we can look at the relative fitness of mutations engineered into every position of the approximately 10,000 base long HIV genome. We are currently adapting this technique to study mechanisms of HIV drug resistance, cross-talk between genes in the HIV genome, and lthe dependence of cell type tropism on viral genomic sequence.